The role of ACKR2 in inflammatory pathologies

Pallas, Kenneth James (2015) The role of ACKR2 in inflammatory pathologies. PhD thesis, University of Glasgow.

Abstract

Chemokines are a highly conserved family of chemoattractant cytokines that are key to the movement of cells around the body under both inflammatory and homeostatic conditions. Chemokines bind to seven transmembrane G protein coupled receptors that signal and induce cell movement upon ligand binding. As well as the ‘classical’ chemokine receptors, there also exists a family of atypical chemokine receptors that do not induce a canonical signalling response upon ligand binding.

These atypical chemokine receptors (ACKR) have been shown to modify the chemokine response through processes such as the scavenging of inflammatory chemokines. One such receptor with this scavenging function is ACKR2 which has been shown to bind and internalise all of the inflammatory CC chemokines. The functional repertoire of ACKR2 continues to be expanded and it is now thought to have a role in inflammation, lymphatic drainage and lymphatic vessel development. It has been shown that the absence of this receptor results in impaired resolution of inflammation and, as a result, increased inflammatory pathologies in vivo. In models of skin inflammation a lack of ACKR2 has been shown to result in increased pathology and impaired inflammatory resolution.

Multiple models of cutaneous inflammation, including excisional wound healing and chemically induced damage, were used to further investigate the role of ACKR2 in this context. Work on wound healing suggested that although ACKR2 appears to play no role in wound closure it does have a role in the formation of scar tissue in an excisional wound. Our data suggest that ACKR2 has a role in collagen deposition in developing and maturing scars. We also found that ACKR2 had a protective role in chemically-induced models of skin inflammation.
We then looked at the role of ACKR2 in ocular inflammation. The main work performed in this section involved the use of the experimental autoimmune uveitis (EAU) model. Here we found that ACKR2 had a protective effective resulting in reduced pathology and infiltration of inflammatory leukocytes. This work also suggested, using in vitro analysis, that a human retinal pigmented epithelial cell line expresses functional ACKR2 protein and that our findings may be relevant to human disease.

Finally we looked at the role of ACKR2 in the inflammatory autoimmune disease rheumatoid arthritis (RA). By taking samples of peripheral blood from RA patients we assessed the transcript levels of Ackr2 and correlated them with clinical measurements. Our findings suggested that, in patients with ‘well-controlled’ RA, there was an increase in the transcription of Ackr2 in peripheral blood leukocytes. Additional work using in vitro methods suggest that the hypoxic nature of the rheumatoid joint, and some of the drugs used to treat the disease, may increase the transcription of Ackr2.

Overall the findings in this work suggest novel roles for ACKR2 in the skin and the eye. They also shed light on further environmental factors that may alter the local expression of ACKR2 in the rheumatoid joint. Taken together this work suggests that ACKR2 may have great therapeutic potential and, furthermore, this potential may be relevant to a wider range of tissues than previously thought.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Chemokine, Immunology, Inflammation, ACKR2, Skin, Eye, Rheumatoid Arthritis
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Graham, Prof. Gerry
• Date of Award: 2015
• Depositing User: Mr Kenneth James Pallas
• Unique ID: glathesis:2015-6807
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 12 Nov 2015 11:00
• Last Modified: 08 Jan 2016 13:04
• URI: https://theses.gla.ac.uk/id/eprint/6807